Journal Article

Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer

Kourula, Stephanie, Amon, Lukas, Pagès, Franck, Fluckiger, Aurélie, Malka, David, Zitvogel, Laurence, Lehmann, Christian H. K., Ly, Pierre, Hollebecque, Antoine, Chamaillard, Mathias, Paillet, Juliette, Dartigues, Peggy, Yonekura, Satoru, Rauber, Conrad, Opolon, Paule, Galon, Jérôme, Roberti, Maria Paula, Vincent, Audrey, Becharef, Sonia, Pizzato, Eugénie, Klein, Christophe, Flament, Caroline, Benoist, Stéphane, Gomperts Boneca, Ivo, Dudziak, Diana, Kroemer, Guido, Ghiringhelli, François, Derosa, Lisa, Marliot, Florence, Scoazec, Jean-Yves, Iebba, Valerio, Eggermont, Alexander, Picard, Marion, Duong, Connie P. M., Routy, Bertrand, Ferrere, Gladys, Van Seuningen, Isabelle, Lepage, Patricia, Vanden Berghe, Tom, Pietrantonio, Filippo, Ryffel, Bernard, Richard, Corentin, Daillère, Romain, Vandenabeele, Peter, Raoult, Didier, Tidjani Alou, Maryam

2020

Overview

The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (T FH ) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of T FH cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of T FH cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1 + T FH cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC. Local microbiome composition influences treatment efficacy of chemotherapy in colon cancer via modulation of tolerogenic versus immunogenic ileal intestinal epithelial cell death, which in turn influences follicular helper T cell priming.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/347 / 631/250/580 / 631/326/2565/2134 / 692/699/67/1059/99 / 692/699/67/1504/1885/1393 / Adenocarcinoma - drug therapy / Adenocarcinoma - immunology / Adenocarcinoma - microbiology / Adenocarcinoma - pathology / Adult / Aged / Aged, 80 and over / Animals / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Apoptosis / Apoptosis - drug effects / Apoptosis - immunology / Bacteroides fragilis / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Cell death / Cell Line, Tumor / Chemotherapy / Colon / Colon cancer / Colonic Neoplasms - drug therapy / Colonic Neoplasms - immunology / Colonic Neoplasms - microbiology / Colonic Neoplasms - pathology / Colorectal cancer / Commensals / Cytokines / Drug therapy / Epithelial cells / Epithelial Cells - drug effects / Epithelial Cells - immunology / Epithelial Cells - pathology / Female / Firmicutes / Gastrointestinal Microbiome - immunology / Gastrointestinal Microbiome - physiology / Health aspects / Humans / Ileum / Ileum - drug effects / Ileum - immunology / Ileum - microbiology / Ileum - pathology / Immunogenic Cell Death - drug effects / Immunogenic Cell Death - immunology / Immunogenicity / Immunologic Surveillance - drug effects / Immunologic Surveillance - immunology / Immunosurveillance / Infectious Diseases / Interleukin 12 / Interleukin-12 - immunology / Intestinal microflora / Intestinal Mucosa / Intestine / Life Sciences / Lymphocytes / Lymphocytes T / Lymphocytes, Tumor-Infiltrating - drug effects / Lymphocytes, Tumor-Infiltrating - immunology / Male / Metabolic Diseases / Mice / Microbiomes / Microbiota / Microbiota (Symbiotic organisms) / Microsatellite instability / Middle Aged / Molecular Medicine / Neurosciences / Oxaliplatin - pharmacology / Oxaliplatin - therapeutic use / PD-1 protein / Physiological aspects / Priming / Prognosis / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Receptors, Interleukin-1 Type I - immunology / T-Lymphocytes, Helper-Inducer - drug effects / T-Lymphocytes, Helper-Inducer - immunology / Tumor-infiltrating lymphocytes